EP1533385A1 - Matrizenabhängigen Verbindungen zur Herstellung von kodierten Molekülen und gesteuerten Verfahren unter Verwendung dieser Verbindungen - Google Patents

Matrizenabhängigen Verbindungen zur Herstellung von kodierten Molekülen und gesteuerten Verfahren unter Verwendung dieser Verbindungen Download PDF

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EP1533385A1
EP1533385A1 EP04077474A EP04077474A EP1533385A1 EP 1533385 A1 EP1533385 A1 EP 1533385A1 EP 04077474 A EP04077474 A EP 04077474A EP 04077474 A EP04077474 A EP 04077474A EP 1533385 A1 EP1533385 A1 EP 1533385A1
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compound
chemical entity
bifunctional chemical
directing element
bifunctional
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French (fr)
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Sanne Schroder Glad
Frank Abilgaard Slok
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Nuevolution AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Definitions

  • the present invention relates to compounds comprising a bifunctional chemical entity, which during formation of an encoded molecule, is positioned in a predominate direction.
  • the positioning in a preferred direction of the bifunctional chemical entity may entail among other things that a full length encoded molecule is formed.
  • the present invention also relates to nucleotide analogues that are substrates for a polymerase and to a double stranded nucleic acid comprising the compounds of the invention.
  • Biological systems allow for the synthesis of ⁇ -peptides by a process known as translation.
  • the natural translation process requires a mRNA template and a plurality of charged tRNA building blocks.
  • a ribosome is initially attached to the mRNA template and directs the recognition between anti-codons of tRNA building blocks and complementing codons of the mRNA template.
  • Concurrently with the recognition process a ⁇ -amino acid residue of the tRNA is reacted with a nascent polypeptide to extent nascent polypeptide with a monomer unit.
  • WO 02/103008 A2 the content of which being incorporated herein in its entirety by reference
  • a method for producing other encoded molecules than ⁇ -peptides.
  • a nucleic acid template and a plurality of nucleoside derivative building blocks carrying a functional entity is provided.
  • complementing nucleoside derivatives are incorporated into a complementary strand.
  • the functional entities are reacted to form an encoded molecule.
  • the end product of the process is a bifunctional complex comprising an encoded molecule attached to the complementing template.
  • the present invention relates to certain aspects of the above publication, especially aspects in which a bifunctional chemical entity is attached to a nucleoside derivative, as a special situation arises when employing bifunctional chemical entities due to a potential free rotation around the linker-nucleotide bond.
  • a bifunctional chemical entity bears two different reactive groups 'X' and 'Y', e.g. both a nucleophile and an electrophile, where 'X' on one chemical entity is meant to react with 'Y' on the neighbour chemical entity, either directly or through a cross-linking agent.
  • the additional bond may be formed directly by one of the functionalities, or the two reactive groups may be attached by separate 'arms' on a fixed backbone. In the first situation the additional bond may be broken during the reaction, whereas the additional bond in the latter should be constructed so that also this bond is cleavable after reaction, to release the final product.
  • the present invention aims at providing compounds which tends to be directed in a predominate direction so that a cluster formation is avoided.
  • directional encoding will lead to full-length products and in addition to products of known polarity.
  • an unambiguous relationship between the genetic information of the template and the encoded molecule may be obtained.
  • the present invention concerns a compound comprising a bifunctional chemical entity attached to a nucleoside derivative and a directing element capable of positioning the bifunctional chemical entity in a predominate direction.
  • DNA made up of a double helix has an inherent twist of the backbone, positioning one base pair not on top of the previous but shifted by a certain distance and in turn rotated by 36 degrees. This means that the distance between neighbouring attachment points is larger (typically on the order of 4.4 ⁇ ) than the vertical distance between two base pairs (3.4 ⁇ ). In addition, the rotation results in different starting directions of the linkers resulting in increasing distance between equal atoms of neighbouring stiff linkers.
  • the functionality placed in the 3' direction of the nucleic acid strand can attack a neighbouring functionality positioned in the 5' direction of the nucleic acid strand or the functionality placed in the 5' direction can attack the neighbouring functionality positioned in the 3' direction of the nucleic acid strand. Due to the twist of DNA these two reactions are geometrically different, and the reaction distance of the 3'-5' reaction is significantly shorter than the reaction distance of the 5'-3' reaction - simply due to the inherent twist of DNA.
  • the present invention takes advantage of the geometry of the DNA double helix, whereby directionality can be obtained without covalently constraining the linkers.
  • the bifunctional chemical entities will be influenced by the DNA environment. By careful design of linkers this can be utilised for directionality purposes.
  • the directing element interacts with one or more major groove atoms or an internucleoside linkage of a double helix nucleic acid.
  • the interaction may be of any appropriate nature, e.g. the directing element is attracted or repulsed by major groove or internucleoside linkage atoms of a nucleic acid double helix.
  • the directing element must interact in a way that positions the bifunctional chemical entity in a certain preferred position.
  • the attraction and/or repulsion may involve interaction between single atoms or between groups of atoms.
  • the interaction between single atoms or groups of atoms may be an ionic attraction or repulsion.
  • the interaction between groups of atoms may involve hydrophobic/hydrophilic interaction, van der Waal interaction etc.
  • preferred or predominate orientation or direction of the bifunctional chemical entity is meant that the bifunctional chemical entity is prone to be positioned in a certain direction in more than 50%, preferably 70% and most preferred 90% of the time.
  • the time a bifunctional entity is in a certain direction may be calculated by evaluating the possibility of each of the possible conformations.
  • conformation refers to individual structural orientations differing by simple rotation about single bonds. Different conformations may in addition give rise to different overall configurations, by which is meant an overall arrangement of bifunctional chemical entities on all modified nucleosides that give rise to one specific direction of reaction.
  • four bifunctional chemical entities arranged with all 'X's' in the same direction corresponds to one specific configuration
  • the directing element may by chosen among a variety of different chemical components.
  • the directing element comprises an optionally substituted 5-, 6-, or 7-membered ring structure.
  • the directing element comprises an aromatic or hetero-aromatic ring system.
  • the extended length between the directing element and the bifunctional chemical entity is 4 ⁇ or less. The term extended length means herein the conformation that leads to the longest distance.
  • the directing element can be positioned relative to the bifunctional chemical entity and the nucleoside derivative in any appropriate way.
  • the directing element is positioned in the linkage between the nucleoside derivative and the bifunctional chemical entity.
  • the bifunctional chemical entity is positioned between a linkage to the nucleoside derivative and the directing element.
  • the directing element is attached to a linkage connecting the bifunctional chemical entity and the nucleoside derivative.
  • the functionalities of the bifunctional chemical entities may be chosen within a wide range of reactive groups.
  • the two functionalities are capable of reacting with each other.
  • the bifunctional chemical entity comprises a nucleophile and an electrophile as the two functionalities.
  • An example of a nucleophlile is an amine and an example of an electrophile is a carboxylic acid or an ester.
  • the functionalities are protected by suitable protection groups.
  • the compound of the invention may be composed solely of the nucleoside derivative, the directing element and the bifunctional chemical entity.
  • the bifunctional chemical entity is attached to the nucleoside derivative through a spacing element.
  • the spacing element serves a variety of functions when present, the main function being distancing the bifunctional chemical entity from the nucleoside derivative.
  • the spacing element comprises a chemical bond which includes electrons from overlapping p-orbitals.
  • the spacing element includes a triple bond, an aromatic- or heteroaromatic ring system, or a hetero atom.
  • the distance between the bifunctional chemical entity and the nucleoside derivative is suitably chosen such that a suitable reactivity is obtained.
  • the extended length between the bifunctional chemical entity and the nucleoside is between 3 and 12 ⁇ .
  • the bifunctional chemical entity can be attached to any position of the nucleotide derivative.
  • the bifunctional chemical entity is attached through a linker to the nucleobase of the nucleoside.
  • the nucleobase derivative may be a naturally occurring nucleobase or a synthetic nucleobase.
  • the nucleobase is selected among adenine, 7-deaza-adenine, uracil, guanidine, 7-deaza-guanidine, thymine, and cytosine.
  • the bifunctional chemical entity is attached through a linker to the 5 position of pyrimidine type nucleobases or the 7 or 8 position of purine type nucleobases.
  • the invention also relates to nucleotide analogues comprising the above nucleotide derivative attached to a bifunctional molecule.
  • the nucleotide analogue may be incoporated into a complementary strand using various means, e.g. chemical ligation or enzymatic polymerisation.
  • a polymerase or a ligase to incorporate the nucleotide analogue. Therefore, the nucleotide analogue is preferably a substrate for a polymerase or a ligase.
  • An example of a substrate for polymerases is nucleotide triphosphates.
  • the nucleotide is usually a mononucleotide triphosphate but may be an oligonucleotide triphosphate as using the teaching of WO 01/16366, the content of which is incorporated herein by reference.
  • An example of a substrate for a ligase is an oligonucleotide monophosphate.
  • the invention is furthermore directed to a method for directing the structural orientation of a bifunctional chemical entity, wherein a nucleoside derivative comprising a bifunctional chemical entity further comprises a directing element capable of positioning the bifunctional chemical entity in a predominate direction.
  • the directing element interacts with the major groove atoms or internucleoside linkage of a double helix nucleic acid. More preferred, the directing element comprises an optionally substituted 5-, 6-, or 7-membered ring structure. In some aspects, the directing element comprises an aromatic or hetero-aromatic ring system.
  • the invention also relates to a method for obtaining an encoded molecule comprising contacting a template nucleic acid with one or a plurality of compounds according to the invention, under conditions that provide for the formation of a complementary template, and reacting the bifunctional chemical entities to form an encoded molecule.
  • the template comprises a sequence of nucleotides which is complemented by the compounds of the invention and incorporated into a complementary strand.
  • a primer is usually initially annealed to the template to obtain a site for the polymerase to bind. Subsequently, each of a plurality of nucleotides is incorporated into a complementary strand by extending the primer.
  • native nucleobases or close analogous are used in the compounds of the invention to obtain a conventional Watson-Crick base pairing scenario, i.e. an A forms a specific base-pair with T and C forms a specific base-pair with G.
  • the specific base-pairing allows the genetic encoding of the bifunctional chemical entity in the final encoded molecule because it is possible to decode the template or alternatively the complementing template to establish the synthesis history of the encoded molecule.
  • a plurality of templates is provided to produce a library of encoded molecules.
  • the library of encoded molecules has a variety of uses, e.g. as possible ligands to a pharmaceutical interesting target or as a vehicle for carrying a pharmaceutical active substance into a tissue or cell of interest.
  • the encoded molecule is generally a polymer in the sense that a head-to-tail reaction of the bifunctional chemical entities occurs. It is to be understood that the units of the polymer may be identical or different and the type of reaction may vary over the encoded molecule.
  • Using a single nucleobase in the compound of the invention allows for four different bifunctional chemical entities, if a one-to- one relationship between the genetic information of the nucleobase and the identity of the bifunctional chemical entity is to be maintained. However, using two or more nucleobases in the compound of the invention allows for the formation of a more diverse monomer composition.
  • the invention also is directed to a double stranded nucleic acid having one or more compounds of the invention incorporated therein.
  • the bifunctional chemical entities have been reacted under conditions in which they had a predominate orientation.
  • one or more linking moieties may be cleaved to efficiently display the encoded molecule.
  • linker as a residue or chemical bond separating the bifunctional chemical entity (BE) and the nucleoside derivative (ND), see Fig. 2.
  • the linker may or may not include a spacing element and/or the directing element.
  • the linker is of a specified length and comprised of two elements: a spacing element (SE) and a directing element (DE), thereby ensuring reaction in the vicinity of the double-stranded DNA (comprised of the template and the linked complementing units) providing a specific overall orientation of bifunctional units and thereby a high degree of directionality of polymerisation.
  • the directing element can be linking the SE and the bifunctional chemical entity (Fig. 3), the DE can be attached the SE as a substituent so that the SE directly links the nucleoside derivative and the BE (Fig. 4), or alternatively, the DE can be attached at the outer side of the BE (Fig. 5).
  • the purpose of the spacing element is to ensure some distance between the BE and the nucleotide derivative typically no more than a favourable van-der-Waal distance just excluding water intrusion between the DNA and the bifunctional chemical entity.
  • the SE is preferably comprised of a chemical unit bearing ⁇ -electrons, i.e. a triple bond, an aromatic or heteroaromatic ring system, or a heteroatom such as O, S, or N.
  • the minimum length of the spacing element is 0 atoms, i.e. the spacing element is absent. When present, the length of the spacing element may be any appropriate number of atoms. Usually, the number of atoms is 6 or less.
  • the purpose of the directing element is to position concurrent bifunctional chemical entities in a consistent manner, e.g. either all horizontally towards the major groove or all vertically towards the major groove. This is achieved through obtaining favourable interactions between major groove atoms of DNA and atoms of the DE and as well between the concurrent DE's. In addition, by use of various substituents, steric hindrance of one but not the other reaction can be achieved.
  • the DE is preferably comprised of a substituted or unsubstituted 5-, 6-, or 7-membered aromatic/heteroaromatic ring system, characterised by potentially having a stacking effect.
  • the DE usually has a minimum length of 3 atoms and a maximum length of 6 atoms. In cases where the DE is attached as a substituent at the SE or at the BE, the typical length is 3 to 6 atoms plus additional atoms from potential ring substituents. If the DE is attached at the outer end of the FE, the link should be through a specifically cleavable traceless construction; typically an orto-nitrobenzyl unit attached an amine.
  • the total linker length (i.e. without the size of the bifunctional entity) is in general from 3 atoms and up to 11 atoms. Combining the different elements in the most efficient way results in a total length (including the bifunctional entity) of between 8 and 15 atoms, resulting in a typical extended length of 8 to 16 ⁇ , and a typical non-extended length of 8-12 ⁇ .
  • This length is comparable to the dimensions of the DNA double helix which has a total diameter of approximately 18 ⁇ , a cross width of the major groove of approximately 17 ⁇ , and a minimum distance between the linker-attachment of the base and the closest phosphate group of the opposite strand of 12.5 ⁇ .
  • a total diameter of approximately 18 ⁇ a cross width of the major groove of approximately 17 ⁇
  • a minimum distance between the linker-attachment of the base and the closest phosphate group of the opposite strand of 12.5 ⁇ .
  • the nucleotides used in the present invention may be linked together in a sequence of nucleotides, i.e. an oligonucleotide.
  • Each nucleotide monomer is normally composed of two parts, namely a nucleobase moiety, and a backbone.
  • the backbone may in some cases be subdivided into a sugar moiety and an internucleoside linker.
  • nucleobase may be selected among naturally occurring nucleobases as well as non-naturally occurring nucleobases.
  • nucleobase includes not only the known purine and pyrimidine hetero-cycles, but also heterocyclic analogues and tautomers thereof.
  • nucleobases are adenine, guanine, thymine, cytosine, uracil, purine, xanthine, diaminopurine, 8-oxo-N 6 -methyladenine, 7-deazaxanthine, 7-deazaguanine, N 4 ,N 4 -ethanocyiosin, N 6 ,N 6 -ethano-2,6-diaminopurine, 5-methylcytosine, 5-(C 3 -C 6 )-alkynylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazolopyridine, isocytosine, isoguanine, inosine and the "non-naturally occurring" nucleobases described in Benner et al., U.S.
  • nucleobase is intended to cover these examples as well as analogues and tautomers thereof.
  • nucleobases are adenine, guanine, thymine, cytosine, 5-methylcytosine, and uracil, which are considered as the naturally occurring nucleobases.
  • backbone units are shown below (B denotes a nucleobase):
  • the sugar moiety of the backbone is suitably a pentose but may be the appropriate part of an PNA or a six-membered ring.
  • Suitable examples of possible pentoses include ribose, 2'-deoxyribose, 2'-O-methyl-ribose, 2'-flour-ribose, and 2'-4'-O-methylene-ribose (LNA).
  • the nucleobase is attached to the 1' position of the pentose entity.
  • internucleoside linker connects the 3' end of preceding monomer to a 5' end of a succeeding monomer when the sugar moiety of the backbone is a pentose, like ribose or 2-deoxyribose.
  • the internucleoside linkage may be the natural occurring phospodiester linkage or a derivative thereof. Examples of such derivatives include phosphorothioate, methylphosphonate, phosphoramidate, phosphotriester, and phosphodithioate.
  • the internucleoside linker can be any of a number of non-phosphorous-containing linkers known in the art.
  • Preferred nucleic acid monomers include naturally occurring nucleosides forming part of the DNA as well as the RNA family connected through phosphodiester linkages.
  • the members of the DNA family include deoxyadenosine, deoxyguanosine, deoxythymidine, and deoxycytidine.
  • the members of the RNA family include adenosine, guanosine, uridine, cytidine, and inosine.
  • Inosine is a non-specific pairing nucleoside and may be used as universal base because inosine can pair nearly isoenergetically with A, T, and C.
  • Other compounds having the same ability of non-specifically base-pairing with natural nucleobases have been formed. Suitable compounds which may be utilized in the present invention includes among others the compounds depicted below
  • Computer calculations can provide a measure of the probability of the two reactions.
  • the purpose of these calculations is to analyse various modes of attack for each linker-BE construction, estimating the most probable reaction and thereby the most probable product. Therefore, the conformational space covered by the linker-BE unit and the zones occupied by the reactive groups needs to be estimated.
  • the conformational space of a specific linker-BE system i.e. the range of the BE, can be estimated by doing a conformational search.
  • Conformational searches can be performed employing various different software products and within these programs using different searching methods, as is standard knowledge within the field.
  • it is not possible to perform a converged conformational search that is, to ensure that enough steps have been taken so that the complete potential energy surface has been covered and thereby that the located minimum energy conformation is truly the global minimum for the molecule.
  • the purpose of these calculations is to get a picture of the space allowed to be covered by a linker-BE unit and thereby to estimate the most likely approach of attack between two BEs and the possibility for the reacting groups to get within reaction distance.
  • Efficient conformational searching methods employing a rather limited number of steps fulfil this purpose.
  • conformations are here meant individual structural orientations differing by simple rotation about single bonds. Different conformations may in addition give rise to different overall configurations, by which is meant an overall arrangement of the two reactive groups on all modified nucleotides that give rise to one specific direction of reaction.
  • the four linker-BE units arranged with all 'X's' in the same direction corresponds to one specific configuration
  • four linker-BE units arranged e.g. with two 'X's' pointing in one direction and the two other in the opposite direction corresponds to another specific configuration.
  • many different conformations are possible, but all of these result in the same 'most probable' product since the overall orientation (direction) of reactive groups is preserved.
  • the structures can be analysed, as follows. It is important to note, that the distances mentioned in the following are reactant distances, i.e. minimum energy distances, and will never be in the range of reaction (i.e. transition state) distances. The possibility therefore exists that the reactant distances for a specific attack seems favourable but that the two groups never can get closer than that, i.e. are incapable of getting within realistic reaction distance. It is therefore necessary to analyse whether the minimum energy structures by simple dihedral rotations will result in structures having the two reacting groups within reaction distance.
  • reactant distances i.e. minimum energy distances
  • a favourable linker design with a large preference for only one of the reactions will thus be shown as having either exclusively large negative or large positive values.
  • Small-value conformations do not constitute a problem with respect to cluster formation but will be 'dead' conformations and as a worst case scenario lead to small overall reaction probability.
  • the relative weight of a conformation decreases with increasing conformation energy, more significance is placed on the lower energy conformations.
  • a favourable linker design will be shown by a large difference between the two numbers. In Figures 7 and 9 the corresponding % directionality number are indicated.
  • Double-stranded DNA with the base sequence 5'-GCTTTTAG-3' (upper strand) was built using HyperChem7 from HyperCube Inc in the most frequent B-conformation.
  • the linker-BE units were built using ChemDraw Ultra 6.0 and Chem3D Ultra 6.0 from ChemOffice. Linker-BE units and DNA were imported into MMOD80. The linkers were then fused to the two mid nucleotides using the build feature in MMOD80, fusing the methyl carbon atom of the T nucleotides with the appropriate linker atom, in effect creating a modified U nucleotide.
  • This orientation results in a reaction distance for the 3' attack (amino group of the topmost bifunctional entity (3' end) reacting with the ester group of the lower building block (5' end)) of 5.5 ⁇ as compared to the distance for the 5' attack (amino group of the lower building block (5' end) reacting with the ester group of the upper building block (3' end)) of 9.5 ⁇ .
  • these structures are minimum energy structures and thus the distances will never be in transition state range (on the order of 2 ⁇ ).
  • a transition state leading to a 3' reaction product will be very close both structurally and energetically to the displayed minimum structure, and a linker leading to a minimum structure showing strong 3' preference (i.e. a significantly shorter d3' than d5') is taken as indicative of that linker being capable of leading to 3' directionality also at the transition structure level.
  • Figure 7 shows the directionality plot of the calculation, according to the reaction distance conversions described in the text above.
  • the plot shows a very clear tendency of this linker to favour a 3' reaction direction, since only very few and high-energy conformations result in positive valued bars.
  • Double-stranded DNA with the base sequence 5'-GCTTTTAG-3' (upper strand) was built using HyperChem7 from HyperCube Inc in the most frequent B-conformation.
  • the linker-FE units were built using ChemDraw Ultra 6.0 and Chem3D Ultra 6.0 from ChemOffice. Linker-FE units and DNA were imported into MMOD80. The linkers were then fused to the two mid nucleotides using the build feature in MMOD80, fusing the methyl carbon atom of the T nucleotides with the appropriate linker atom, in effect creating a modified U nucleotide.
  • Example 4 Examples of general linker construction of the type ND-SE-DE-FE
  • Example 5 Examples of general linker constructions of the type
  • Example 6 Examples of general linker constructions of the type ND-SE-BE-DE

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EP04077474A 2003-09-05 2004-09-06 Matrizenabhängigen Verbindungen zur Herstellung von kodierten Molekülen und gesteuerten Verfahren unter Verwendung dieser Verbindungen Withdrawn EP1533385A1 (de)

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US7727713B2 (en) 2001-06-20 2010-06-01 Nuevolution A/S Templated molecules and methods for using such molecules
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US10730906B2 (en) 2002-08-01 2020-08-04 Nuevolutions A/S Multi-step synthesis of templated molecules
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